AbstractTo date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8⁺ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led—in the absence of lymphodepletion or exogenous cytokine support—to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8⁺ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.